Regulation of gene expression is central to efficient biological function. Two key aspects of this process are the synthesis of mRNA (transcription) and control of its stability. The goal of this proposal is to understand how an important class of proteins, the CCCH zinc finger proteins of the tristetraprolin (TTP) family, recognizes and binds to mRNA to promote its degradation. This process provides an important mechanism for reducing the synthesis of key cytokines and growth factors that regulate inflammation and the initiation and progression of cancer. To understand the function and regulation of TTP in the cell we will use an integrated approach that combines NMR spectroscopy, computer simulation, biochemical and in vivo experiments. Our detailed biophysical and biochemical characterizations of TTP-mRNA interactions will determine the mechanism of TTP-mediated mRNA destabilization that is relevant for cancer and inflammation. PUBLIC HEALTH RELEVANCE: TTP is an important protein for limiting the production of cytokines and growth factors involved in tumor growth and progression and in chronic inflammation. This study will improve our understanding of the mechanisms by which TTP regulates the production of proteins related to these diseases, and will give us a new understanding of the molecular basis of cancer and chronic inflammation.